CHOLINERGIC SYSTEM pdf - د. سمير

Sunday 19 / 10 / 2014

@Ali Kareem 2014-2015

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CHOLINERGIC SYSTEM

Lecture 3

Total lectures NO. 5

Dr. Samer Matloub

Lec:3

Cholinergic Antagonists

"cholinoceptor blockers"

Anti Muscarinics

Anti Nicotinics

M1 selective

Nonselective Ganglion blockers N-M blockers

Muscarinic Antagonists:



These agents (e.g. Atropine & Scopolamine) act as competitive

"surmountable" pharmacological antagonists.



They block muscarinic receptors causing inhibition of all muscarinic

functions and their blocking effects are overcome by increasing the
concentration of Ach or by other muscarinic agonists.



These drugs also block the few exceptional sympathetic neurons that are

cholinergic "e.g. sweat gland" .



These drugs have little or no effect on the autonomic ganglia or the N-M

junction.



Most of these drugs are nonselective for muscarinic receptors except for

pirenzepine and telenzepine which are M1 selective (used in treatment
of peptic ulcers).



The action of muscarinic blockers (e.g. atropine) is mostly predictable

effects derived from cholinoceptor blockade.

Effects of muscarinic blocking drugs:

Organs

Effect

Mechanism

CNS

Sedation, anti motion sickness
action, anti parkinsonian action,
amnesia, delirium.

Block of MRs, unknown
subtype.

Eye

Mydriasis, cycloplegia (paralysis
of accommodation)

Block of M3 Rs

Bronchi

Bronchodilatation esp. if
constricted.

Block of M3 Rs

GIT

Relaxation, slowed peristalsis.

Block of M1,M3 Rs

Genito-
urinary tract

Relaxation of the bladder wall,
Urinary retention.

Block of M3 Rs

Heart

Initial bradycardia, esp. at low
doses then tachycardia.

Tachycardia from block of
M2 R in the heart.

Blood vessels

Block of muscarinic
vasodilatation , not manifested
unless a muscarinic agonist is
present.

Block of M3 Rs on
endothelium of B.Vs

Glands

Marked reduction of salivation,
lacrimation,sweating, less
reduction of gastric secretion.

Block of M1, M3
receptors.

Skeletal m.

none

Notes:

 CNS effects are less predictable. CVS effects at therapeutic doses include an
initial  slowing  of  the  heart  rate  caused  by  a  central  mechanism  (medullary
stimulation  of  the  cardiac  inhibitory  centre)  or  more  likely  by  presynaptic
vagal  effects  (blocking  the  presynaptic  M1R  on  vagal  post  ganglionic  fibers
that  normally  limit  Ach  release  in  the  SA  node).this  slowing  is  followed  by
tachycardia  and  decrease  AV  conduction  time  as  it  would  be  predicted  from
peripheral vagal blockade (blocking of M2 receptors in the heart).

  The  effect  on  the  blood  vessels  include  blockade  of  the  endothelial
muscarinic  receptors  that  mediate  vasodilatation  and  also  vasodilatation
produced by sympathetic cholinergic nerve stimulation to the skeletal muscle
vascular  bed.  However  there  is  a  little  effect  on  blood  pressure  of  normal
persons.  At  toxic  doses  atropine  may  cause  cutaneous  vasodilatation  in  the
upper part of the body, the mechanism is unknown.

Clinical uses of muscarinic antagonists:

Note:

topical activity (the ability to enter the eye after conjuctival

administration)  and  similar  ability  to  cross  lipid  barrier  (e.g.  BBB)  is
important in determining the usefulness of several antimuscarinics often used
in  ophthalmology  and  in  Parkinsonism.  In  contrast  the  antimuscarinic  drugs
used  for  their  antisecretory  or  antispasmodic  actions  in  the  gut  or  in  the
bronchi  are  often  selected  for  minimum  CNS  activity  (these  drugs  may
incorporate quaternary amine group to limit penetration to the CNS).

1-CNS:

- Motion sickness: scopolamine is the standard therapy in motion

sickness.

Parkinsonism: Benztropine, biperidine, trihexphenidyl (these drugs
are mainly effective to control tremors).

 Benztropine is sometimes used to treat acute dystonias caused by
antipsychptic drugs.

2- Eye:

are used to dilate the pupil (mydriasis) and to paralyze

accommodation (cycloplegia).
Drugs used to this purpose include (in descending order of duration of
action).

Atropine < 72 hours, homatropine (24 hrs.), cyclopentolate (2-12 hrs.),
tropicamide (0.5-4 hrs.).

3-Bronchi:

Parentral atropine has been used to reduce airway secretion

during surgery. Ipratropium a quaternary agent is used by inhalation to
reduce bronchoconstriction in asthma and COPD (chronic obstructive
pulmonary disease). This drug has very few antimuscarinic effects outside the
lung because it is rapidly metabolized and poorly absorbed. it is less effective
than B

agonists in this regard.

4- CVS:

Parentral atropine and similar antimuscarinics are used to  H.R

in cases of bradychardia due to depression of the SA node or the AV node
function (e.g. after myocardial infarction (MI) and in persons with
hyperactive carotid sinus reflexes).

5- Gut:

Atropine, methscopolamine and propantheline were used in the

past in acid peptic disease to reduce acid secretion (volume, amount of acid
and pepsin and mucin are all reduced but large doses are required).



These drugs are less effective than the H2 antagonist (e.g. cimitidine)

and produce frequent side effects.



Pirenzepine and telenzepine are M

, selective antagonist, may be more

useful in peptic ulcer (M

receptors are present on the ECL cells and not

on parietal cells which possess M

R.)



Muscarinic antagonist e.g. glycopyrolate, dicyclomine, hyoscin butyl

bromide and methscopolamine can be used to reduce cramping
(antispasmodic) and hepermotility in transient diarrheas but
diphenoxylate (an opioid) is more effective.

6- Urinary system:

Oxybutynin, glycopyrolate, dicyclomine are used

in the treatment of spasm and urgency induced by mild inflammation e.g.
(cystitis), surgery and neurological conditions but can precipitate urinary
retention in elderly men with benign prostatic hyperplasia (Bph).

 Tolterodine (is an M

selective antimuscarinic) is used in adult with

urinary incontinence.

7- Other uses

: As an antidote for cholinergic agonists atropine is used in

the treatment of organophosphorus poisoning and some types of mushroom
poisoning.Atropine because of its ability to enter CNS is used to block the
effect of excess Ach resulting from inhibition of ChE by drugs such as
physostigmine.

Atropine:

Is the protypical non selective muscarinic blocker , It is an alkaloid found

in atropa belladonna. It is a tertiary amine (lipid soluble and crosses to the
CNS). It is eliminated partly by metabolism and by renal excretion t ½ is 2
hrs., Duration of action is 4-8 hrs except in the eye where the effect lasts for
72 hrs. or longer. the antidote in atropine poisoning is physostigmine.

Scopolamine (hyoscine):

Is another belladonna alkaloid similar to atropine but has a longer duration
of action and greater action on the CNS. It produces sedation. Its use is limited
for the prevention and treatment of motion sickness.

Adverse effects and toxicity:

Most of the adverse effects are predictable antimuscarinic effects, although
there are some unpredictable actions.

 Predictable include: Dry mouth, blurred vision, tachycardia, constipation,
hyperthermia due to blockage of thermo-regulatory sweating also called
atropine fever (this occurs esp. in infants which may be dangerous.)

 Atropine toxicity is described as feeling as dry as a bone because

sweating, salivation and lacrimation are reduced or stopped. In the elderly
atropine may cause acute angle-closure glaucoma and urinary retention esp.
in patients with Bph (benign prostatic hyperplasia)

 Unpredictable include:

1- CNS toxicity which includes: sedation, amnesia and delirium or
hallucination (described as mad as a hatter) convulsions may also occur.

2- CVS which include: intra ventricular conduction block and cutaneous
vasodilatation of the vessels of head, neck, arms and trunk (atropine flush)
which is described as red as beet, which may be diagnostic.

Contra indications:

These drugs should be cautiously used in infants (hyperthermia) these

drugs are relatively CI in patients with glaucoma and in men with Bph.